Two broad objectives encompassing the metabolism and action of estrogens in pregnancy and cancer are central to the proposed work. The metabolism studies would focus on estriol conjugates in blood and urine of normal pregnancy and pregnancy complicated by renal or hepatic disease. Prostaglandin-induced labor and other states exhibiting abnormally high or fluctuating plasma estriol levels will be studied in the same way. Similar measurements will be made in the blood and breast cyst fluid in non pregnant women. Of particular interest is the origin of the the high concentration of estriol-3-sulfate in the cyst fluid. Sera from women at high risk for breast cancer will be analyzed for estriol, estrone and estradiol and their conjugates. Comparisons will be made with normal controls. The model for hormone action under study is the uterine trypsin-like protease expressed by the estradiol treated rodent. The enzyme will be isolated, purified and its properties studied. The influence of the protease will be evaluated by applying potent protease inhibitors to in vivo and in vitro systems and examining selected biochemical and physiological endpoints in the uterus. Specimens of human endometrium will be investigated in a manner designed to test the relevance of the animal model to the understanding of uterine function in the human. Also, the relationships of proteases and their inhibitors will be explored in cell cultures of estrogen-dependent rat mammary cancer. These models focus on the possible control of hormone-related tumors and fertility by non hormonal agents.